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Cognitive-behavioural models of excessive fatigue suggest that people who believe that failure to meet high standards indicates unacceptability to others (a form of ‘negative perfectionism’) are at risk of fatigue after a period of illness or stress. The present study investigates this using a prospective design and possible mediating factors between such beliefs and fatigue were also investigated. Undergraduate students completed questionnaires at the beginning of the academic year (time 1; n = 436) and again following a time of academic pressure, 16 weeks later (time 2; n = 206). Participants were significantly more fatigued at time 2 than at time 1. Negative perfectionism was positively associated with all measures of fatigue and predicted subsequent levels of physical fatigue after controlling for time 1 fatigue. Time 1 negative perfectionism was not associated with time 2 perfectionist studying behaviours, distress about academic work or specific health behaviours, but was associated with time 2 depression. Results also indicated that time 2 depression may account for the relationship between baseline negative perfectionism and subsequent fatigue. This is the first prospective study to demonstrate a significant relationship between perfectionism and subsequent fatigue.